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Acta Neuropathol. 2016 Apr;131(4):587-604. doi: 10.1007/s00401-016-1544-2. Epub 2016 Feb 19.

Monomethylated and unmethylated FUS exhibit increased binding to Transportin and distinguish FTLD-FUS from ALS-FUS.

Suárez-Calvet M1,2,3, Neumann M4,5, Arzberger T6,7,2, Abou-Ajram C1,8, Funk E1, Hartmann H2,9, Edbauer D2,9, Kremmer E10, Göbl C11,12, Resch M11,12, Bourgeois B11,12, Madl T11,12,13,14, Reber S15,16, Jutzi D15, Ruepp MD15, Mackenzie IR17, Ansorge O18, Dormann D19,20,21, Haass C22,23,24.

Author information

1
Biomedical Center (BMC), Biochemistry, Ludwig-Maximilians-University Munich, Feodor-Lynen Strasse 17, 81377, Munich, Germany.
2
German Center for Neurodegenerative Diseases (DZNE) Munich, Feodor-Lynen Strasse 17, 81377, Munich, Germany.
3
Universitat Autònoma de Barcelona, 08193, Bellaterra, Barcelona, Spain.
4
Department of Neuropathology, University of Tübingen, 72076, Tübingen, Germany.
5
DZNE, German Center for Neurodegenerative Diseases, 72076, Tübingen, Germany.
6
Department of Psychiatry and Psychotherapy, Ludwig-Maximilians-University Munich, 80336, Munich, Germany.
7
Center for Neuropathology and Prion Research, Ludwig-Maximilians-University Munich, 81377, Munich, Germany.
8
BioMedical Center (BMC), Lehrstuhl Zellbiologie (Anatomie III), Großhaderner Strasse 9, 82152, Planegg-Martinsried, Germany.
9
Munich Cluster for Systems Neurology (SyNergy), 81377, Munich, Germany.
10
Institute of Molecular Immunology, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), 81377, Munich, Germany.
11
Department of Chemistry, Center for Integrated Protein Science Munich (CIPSM), Technische Universität München, Lichtenbergstr.4, 85747, Garching, Germany.
12
Institute of Structural Biology, Helmholtz Zentrum München, 85764, Neuherberg, Germany.
13
Institute of Molecular Biology and Biochemistry, Center of Molecular Medicine, Medical University of Graz, 8010, Graz, Austria.
14
Omics Center Graz, BioTechMed, 8010, Graz, Austria.
15
Department of Chemistry and Biochemistry, University of Bern, 3012, Bern, Switzerland.
16
Graduate School for Cellular and Biomedical Sciences, University of Bern, 3012, Bern, Switzerland.
17
Department of Pathology, Vancouver General Hospital, University of British Columbia, Vancouver, Canada.
18
Department of Neuropathology, John Radcliffe Hospital, Oxford, UK.
19
Biomedical Center (BMC), Biochemistry, Ludwig-Maximilians-University Munich, Feodor-Lynen Strasse 17, 81377, Munich, Germany. dorothee.dormann@med.uni-muenchen.de.
20
BioMedical Center (BMC), Lehrstuhl Zellbiologie (Anatomie III), Großhaderner Strasse 9, 82152, Planegg-Martinsried, Germany. dorothee.dormann@med.uni-muenchen.de.
21
Munich Cluster for Systems Neurology (SyNergy), 81377, Munich, Germany. dorothee.dormann@med.uni-muenchen.de.
22
Biomedical Center (BMC), Biochemistry, Ludwig-Maximilians-University Munich, Feodor-Lynen Strasse 17, 81377, Munich, Germany. christian.haass@mail03.med.uni-muenchen.de.
23
German Center for Neurodegenerative Diseases (DZNE) Munich, Feodor-Lynen Strasse 17, 81377, Munich, Germany. christian.haass@mail03.med.uni-muenchen.de.
24
Munich Cluster for Systems Neurology (SyNergy), 81377, Munich, Germany. christian.haass@mail03.med.uni-muenchen.de.

Abstract

Deposition of the nuclear DNA/RNA-binding protein Fused in sarcoma (FUS) in cytosolic inclusions is a common hallmark of some cases of frontotemporal lobar degeneration (FTLD-FUS) and amyotrophic lateral sclerosis (ALS-FUS). Whether both diseases also share common pathological mechanisms is currently unclear. Based on our previous finding that FUS deposits are hypomethylated in FTLD-FUS but not in ALS-FUS, we have now investigated whether genetic or pharmacological inactivation of Protein arginine methyltransferase 1 (PRMT1) activity results in unmethylated FUS or in alternatively methylated forms of FUS. To do so, we generated FUS-specific monoclonal antibodies that specifically recognize unmethylated arginine (UMA), monomethylated arginine (MMA) or asymmetrically dimethylated arginine (ADMA). Loss of PRMT1 indeed not only results in an increase of UMA FUS and a decrease of ADMA FUS, but also in a significant increase of MMA FUS. Compared to ADMA FUS, UMA and MMA FUS exhibit much higher binding affinities to Transportin-1, the nuclear import receptor of FUS, as measured by pull-down assays and isothermal titration calorimetry. Moreover, we show that MMA FUS occurs exclusively in FTLD-FUS, but not in ALS-FUS. Our findings therefore provide additional evidence that FTLD-FUS and ALS-FUS are caused by distinct disease mechanisms although both share FUS deposits as a common denominator.

KEYWORDS:

Amyotrophic lateral sclerosis (ALS); Arginine methylation; Frontotemporal lobar degeneration (FTLD); Fused in sarcoma (FUS); Neurodegeneration; Protein arginine methyltransferase 1 (PRMT1); Transportin-1

PMID:
26895297
DOI:
10.1007/s00401-016-1544-2
[Indexed for MEDLINE]

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